- Pseudorabies Virus Induces Autophagy to Enhance Viral Replication in Mouse Neuro-2a cells In Vitro. [Journal Article]
- VRVirus Res 2018 Feb 13
- Autophagy of cytoplasmic components plays an essential role in the pathogenic infection process. Furthermore, research suggests that autophagy is an extremely important component of the innate immune...
Autophagy of cytoplasmic components plays an essential role in the pathogenic infection process. Furthermore, research suggests that autophagy is an extremely important component of the innate immune response. Our study aimed to reveal the effect of virus-induced autophagy on pseudorabies virus (PRV) replication. Our results confirmed that light chain 3 (LC3)-I was converted into LC3-II after PRV infection; this transition is considered an important indicator of autophagy. Transmission electron microscopy (TEM) revealed that PRV infection could notably increase the number of autophagosomes in mouse neuro-2a (N2a) cells. In addition, LC3-II accumulated in response to chloroquine (CQ) treatment, indicating that PRV infection induced a complete autophagic flux response. Furthermore, our analyses verified differences in the magnitude of autophagy induction by two different PRV isolates, LA and ZJ01. Subsequent analysis showed that the induction of autophagy by rapamycin facilitated PRV replication, while inhibition of autophagy by 3-methyladenine (3-MA) reduced PRV replication. These results indicated that PRV induced autophagy via the classical Beclin-1-Atg7-Atg5 pathway to enhance viral replication in N2a cells in vitro.
- Autophagy inhibition enhances anticancer efficacy of artepillin C, a cinnamic acid derivative in Brazilian green propolis. [Journal Article]
- BBBiochem Biophys Res Commun 2018 Feb 13
- Propolis, a resinous substance produced by honeybees, possesses various biological actions including anticancer activity towards tumor cells. Recently, the ethanol extract of Brazilian green propolis...
Propolis, a resinous substance produced by honeybees, possesses various biological actions including anticancer activity towards tumor cells. Recently, the ethanol extract of Brazilian green propolis has been shown to induce autophagy, which is known to be induced in treatment of cancer cells with anticancer drugs, leading to cancer cell survival and decreased sensitivity to anticancer agents. In this study, we aimed to identify autophagy-inducing components of the propolis and elucidated the reciprocal relationship between anticancer cytotoxicity and protective autophagy in prostate cancer CWR22Rv1 cells. Among eight cinnamic acid derivatives [chlorogenic acid, p-coumaric acid, caffeic acid, 3,4-caffeoylquinic acid, artepillin C (ArtC), baccharin, drupanin and caffeic acid phenethyl ester] in propolis, only ArtC showed high autophagy-inducing activity accompanying LC3-II upregulation. ArtC was also induced apoptosis as revealed by DNA fragmentation and increases in cleaved caspase-3 and poly ADP-ribose polymerase. The apoptosis induced by ArtC was exacerbated by cotreatment with autophagy inhibitors (chloroquine, wortmannin and U0126). The cotreatment further induced necroptosis accompanying increased expression of receptor-interacting serine/threonine protein kinases 1 and 3. These data indicate that cytotoxicity of ArtC to the prostate cancer cells is dampened by induced autophagy, but is markedly augmented by inhibition of autophagy. Therefore, the combination of ArtC and autophagy inhibitors may be a novel complementary-alternative treatment for prostate cancer.
- Predictive and preventive significance of AMPK activation on hepatocarcinogenesis in patients with liver cirrhosis. [Journal Article]
- CDCell Death Dis 2018 Feb 15; 9(3):264
- Metformin has been demonstrated to prevent hepatocellular carcinoma (HCC). Metformin acts mainly by phosphorylation of AMPK. However, the phosphorylation status of AMPK and its role in the prediction...
Metformin has been demonstrated to prevent hepatocellular carcinoma (HCC). Metformin acts mainly by phosphorylation of AMPK. However, the phosphorylation status of AMPK and its role in the prediction and prevention of HCC in cirrhotic patients remains unclear. The phosphorylation status of AMPK (Thr172) was determined by immunostaining in tissue microarrays of 426 cirrhotic liver tissues. Low expression of p-AMPK was observed in 94 (22.1%) cases. The median follow-up time was 87 months. HCC occurrence probability at 1/3/5/10 years after Hassab procedure was 3.1/9.6/13.8/30.6% in patients with p-AMPK low expression and 0/0.3/0.3/8% in patients with p-AMPK high expression, respectively. HCC occurrence risk was significantly higher in patients with p-AMPK low expression in univariable analysis (HR, 6.25; 95% CI: 3.36-11.60; P < 0.001) and multivariable analysis (HR, 6.0; 95% CI: 3.24-11.10; P < 0.001). An independent external cohort validated the significance of p-AMPK low expression. In addition, in vivo experiments demonstrated that AMPK activation status was negatively related to HCC occurrence and blocking autophagy by chloroquine counteracted the protective effect of AMPK phosphorylation. These results present novel insight into a critical predictive role of AMPK activation in hepatocarcinogenesis and AMPK activation seems to be a potential target for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.
- Impaired autophagic flux is associated with the severity of trauma and the role of A2AR in brain cells after traumatic brain injury. [Journal Article]
- CDCell Death Dis 2018 Feb 14; 9(2):252
- Recent studies have shown that after traumatic brain injury (TBI), the number of autophagosomes is markedly increased in brain cells surrounding the wound; however, whether autophagy is enhanced or s...
Recent studies have shown that after traumatic brain injury (TBI), the number of autophagosomes is markedly increased in brain cells surrounding the wound; however, whether autophagy is enhanced or suppressed by TBI remains controversial. In our study, we used a controlled cortical impact system to establish models of mild, moderate and severe TBI. In the mild TBI model, the levels of autophagy-related protein 6 (Beclin1) and autophagy-related protein 12 (ATG12)-autophagy-related protein 5 (ATG5) conjugates were increased, indicating the enhanced initiation of autophagy. Furthermore, the level of the autophagic substrate sequestosome 1 (SQSTM1) was decreased in the ipsilateral cortex. This result, together with the results observed in tandem mRFP-GFP-LC3 adeno-associated virus (AAV)-infected mice, indicates that autophagosome clearance was also increased after mild TBI. Conversely, following moderate and severe TBI, there was no change in the initiation of autophagy, and autophagosome accumulation was observed. Next, we used chloroquine (CQ) to artificially impair autophagic flux in the injured cortex of the mild TBI model and found that the severity of trauma was obviously exacerbated. In addition, autophagic flux and trauma severity were significantly improved in adenosine A2Areceptor (A2AR) knockout (KO) mice subjected to moderate TBI. Thus, A2AR may be involved in regulating the impairment of autophagic flux in response to brain injury. Our findings suggest that whether autophagy is increased after TBI is associated with whether autophagic flux is impaired, and the impairment of autophagic flux exacerbates the severity of trauma. Furthermore, A2AR may be a target for alleviating the impairment in autophagic flux after TBI.
- CREB3 Regulatory Factor -mTOR-autophagy regulates goat endometrial function during early pregnancy. [Journal Article]
- BRBiol Reprod 2018 Feb 13
- In domestic ruminants, a receptive endometrium is crucial for successful pregnancy. Although many essential molecular modulators and pathways have been identified during early pregnancy, the precise ...
In domestic ruminants, a receptive endometrium is crucial for successful pregnancy. Although many essential molecular modulators and pathways have been identified during early pregnancy, the precise mechanisms regulating goat endometrial function remains largely unknown. Here, we describe a novel regulator during early pregnancy, whereby hormones increased CREB3 Regulatory Factor (CREBRF) expression and act as a potential activator of autophagy in endometrial epithelial cells (EECs) via the mTOR pathway. Our results showed that knockdown of CREBRF via shCREBRF hampered EECs proliferation by S-phase cell cycle arrest and significantly inhibited endometrial function. We also reported that CREBRF-mTOR-autophagy pathway plays a vital role in regulating endometrial function, with a blockade of the mTOR by rapamycin demonstrating the regulatory function on prostaglandin (PGs) secretion and cell attachment in EECs. Moreover, chloroquine (CQ) pretreatment also proved the above conclusion. Collectively, our findings provide new insight into the molecular mechanisms of goat endometrial function and indicate that the CREBRF-mTOR-autophagy pathway plays a central role in PGs secretion and cell attachment.
- Synthesis of Cyclic Peptides as Potential Anti-Malarials. [Journal Article]
- ACACS Comb Sci 2018 Feb 15
- The results from the synthesis of peptides by Fmoc/SPPS on a 2-CTC resin and then lactamization in solution or solid phase for the preparation of cyclopeptides are presented. Both procedures allow th...
The results from the synthesis of peptides by Fmoc/SPPS on a 2-CTC resin and then lactamization in solution or solid phase for the preparation of cyclopeptides are presented. Both procedures allow the synthesis of the desired compounds in good to very good yield and with high cyclization efficiency for on-resin macrocyclization. In addition, the activities of the corresponding cyclopeptides against the chloroquine-resistant K1 strain of Plasmodium falciparum were evaluated. Cyclo-Cys(Trt)-Gly-Thr(tBu)-Gly-Cys(Trt)-Gly showed potent in vitro and selective activity against this parasite, EC50 = 28 nM.
- Cigarette Smoke Exposure Inhibits Bacterial Killing via TFEB-Mediated Autophagy Impairment and Resulting Phagocytosis Defect. [Journal Article]
- MIMediators Inflamm 2017; 2017:3028082
- CONCLUSIONS: Our data suggests that CS-mediated autophagy impairment as a critical mechanism involved in the resulting phagocytic defect, as well as the therapeutic potential of autophagy-inducing drugs in restoring is CS-impaired phagocytosis.
- Lup-20(29)-en-3β,28-di-yl-nitrooxy acetate affects MCF-7 proliferation through the crosstalk between apoptosis and autophagy in mitochondria. [Journal Article]
- CDCell Death Dis 2018 Feb 14; 9(2):241
- Betulin (BT), a pentacyclic lupine-type triterpenoid natural product, possesses antitumor activity in various types of cancers. However, its clinical development was discouraged due to its low biolog...
Betulin (BT), a pentacyclic lupine-type triterpenoid natural product, possesses antitumor activity in various types of cancers. However, its clinical development was discouraged due to its low biological activities and poor solubility. We prepared lup-20(29)-en-3β,28-di-yl-nitrooxy acetate (NBT), a derivative of BT, that was chemically modified at position 3 of ring A and C-28 by introducing a NO-releasing moiety. This study mainly explored the mechanism of NBT in treating breast cancer through the crosstalk between apoptosis and autophagy in mitochondria. NBT possessed a potent antiproliferative activity in MCF-7 cells both in vitro and in vivo. Mechanically, NBT affected cell death through the mitochondrial apoptosis pathway and autophagy. NBT induced cell cycle arrest in the G0/G1phase by decreasing the expression of cyclin D1. It also induced mitochondrial apoptosis by increasing the expression of Bax, caspase-9, and poly(ADP-ribose) polymerase and mitochondrial membrane potential loss and leaks of cytochrome c (Cyt C) from mitochondria in MCF-7 cells and decreasing the expression of mitochondrial Bcl-2. We further demonstrated whether chloroquine (CQ), which inhibits the degradation of autophagosome induced by NBT, affects the proliferation of MCF-7 cells compared with NBT. The experiments inferred that the combination of NBT and CQ significantly promoted MCF-7 cell mitochondria to divide and Cyt C to be released from mitochondria to the cytoplasm, resulting in an increased apoptosis rate. The in vivo experiments showed that NBT inhibited the growth of MCF-7 tumor via the apoptosis pathway, and its effect was similar to 5-fluorouracil.
- Promising approach to reducing Malaria transmission by ivermectin: Sporontocidal effect against Plasmodium vivax in the South American vectors Anopheles aquasalis and Anopheles darlingi. [Journal Article]
- PNPLoS Negl Trop Dis 2018 Feb 14; 12(2):e0006221
- CONCLUSIONS: In conclusion, whole blood spiked with IVM reduced the infection rate of P. vivax in An. aquasalis and An. darlingi, and increased the mortality of mosquitoes. Plasma from healthy volunteers after IVM administration affect asexual P. vivax development. These findings support that ivermectin may be used to decrease P. vivax transmission.
New Search Next
- Prediction model for anti-malarial activities of hemozoin inhibitors using physicochemical properties. [Journal Article]
- AAAntimicrob Agents Chemother 2018 Feb 12
- The rapid spread of strains of malaria parasites resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the anti-malarial activity of chemical c...
The rapid spread of strains of malaria parasites resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the anti-malarial activity of chemical compounds possessing anti-hemozoin formation activity as a new means of anti-malarial drug discovery. After the initialin vitroanti-hemozoin formation high-throughput screening (HTS) of 9,600 compounds, a total of 224 hit compounds were identified as hemozoin inhibitors. These 224 compounds were tested forin vitroerythrocytic anti-malarial activity at 10 μM using the chloroquine-mefloquine sensitivePlasmodium falciparumstrain, 3D7A. Two independent experiments were conducted. The physicochemical properties of the active compounds were extracted from ChemSpider and SciFinder databases. We analyzed the extracted data using Bayesian model averaging (BMA). Our findings revealed that lower numbers of S atoms, lower values of log D pH 3, 4 and 5, and higher values of ACD log D pH 7.4 had a significant association with anti-malarial activity among compounds possessing anti-hemozoin formation activity. The BMA model revealed an accuracy of 91.23%. We report new prediction models containing the physicochemical properties that shed light on effective chemical groups for synthetic anti-malarial compounds and helpin silicoscreening for novel anti-malarial drugs.